Adenosine triphosphate (ATP) is well-recognized as the primary energy currency of living cells, but has also emerged as a significant signaling molecule that can shape physiological and pathophysiological processes by interacting with any of several ‘purinergic’ membrane-associated receptor molecules. The purinergic receptor family comprises both G-protein-coupled (GPCR) receptors (assigned a P2Y nomenclature) and ligand-gated ion channel (P2X) variants. ATP elicits an excitatory effect on afferent sensory nerves via an interaction with receptors of the P2X subfamily. The consequence of such hyperexcitability may be interpreted as pain when the ATP effect is elicited in skin, bone or visceral tissues, as pain and/or cough in airway tissues, or as pain and/or instability when it occurs in the bladder. See Ford, Purinergic Signalling, 8 (Suppl 1), S3-S26, 2012; Ford et al., Frontiers in Cellular Neuroscience, Volume 7, Article 267, 2013. Two particular receptor variants within the P2X subfamily, designated P2X3 and P2X2/3, have emerged as targets of particular interest in a variety of studies designed to measure nociception, airway or bladder function in rodents, since activation of these receptors by ATP is capable of generating the adverse events cited above.
Accordingly, there is a need for more potent and selective P2X3/P2X2/3 modulators.